Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
The incidence of conditions such as stroke and dementia are more closely related to the level of systolic blood pressure than diastolic blood pressure. Elevations in systolic blood pressure have been thought to occur as a consequence of decreased production of the intrinsic vasodilator endothelial derived relaxing factor (EDRF) or nitric oxide (NO) resulting in increased vascular tone or vasoconstriction. This explains increases in systolic blood pressure but does not explain the falling diastolic blood pressure and the widened pulse pressure that are associated with increased cardiovascular risk. Only structural changes in the major blood vessel, the aorta, which reduce compliance and thus reduce the ability of the aorta to relax and absorb the systolic pressure wave as well as to undergo elastic recoil during cardiac filling or diastole can explain this phenomenon. Loss of elastic fibres and their replacement by collagen as well as disruption of the smooth muscle fibres by increased amounts of collagen and fibrous tissue result in a decrease in elasticity and compliance. These changes in the aortic wall cause rigidity which in turn results in a reflectance wave in response to the pressure wave of cardiac systole. The effect of the reflectance wave is to augment and further increase systolic blood pressure. The increased rigidity also prevents elastic recoil during cardiac filling, attenuates the capacity of the vasculature to maintain blood pressure in diastole, and results in a lower diastolic pressure. The difference between systolic and diastolic pressures is termed the pulse pressure. A widened pulse pressure (>90 mmHg) denotes high absolute risk for cardiovascular events such as stroke.
Currently available blood pressure lowering agents address the increased vasoconstrictor component of systolic pressure and lower both systolic and diastolic pressures by similar amounts. The failure of these agents to effect structural remodelling in the aorta means, that in patients with a widened pulse pressure, treatment is limited by diastolic pressure reductions. As a consequence, systolic blood pressure often remains above recommended target levels. Thus pulse pressure remains widened despite treatment or may be exacerbated by it and such patients remain at high risk for cardiovascular events such as stroke.
There is thus a need for therapeutic agents which will prevent and/or reverse the structural changes to the aorta.
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.